Studies conducted in this laboratory have revealed that tricyclic antidepressant drugs effectively inhibit rabbit mitochondrial monoamine oxidase (MAO). Since it is conceivable that inhibition of this oxidase could be involved in the clinical action of these antidepressant agents, the following studies with MAO isolated from human brain are proposed: 1) Determine the extent to which clinically important tricyclic antidepressant drugs and structurally related tricyclic compounds inhibit the different forms of human brain mitochondrial MAO. 2) Assess the structural features of these tricyclic drugs which facilitate their binding the oxidases. 3) Characterize the nature of the interaction between the tricyclic drugs and the different forms of human MAO. The proposed study will employ three different preparations of the human brain oxidase (crude mitochondria, outer mitochondrial membranes, and the purified isoenzymes). Methods used to measure MAO activity with the rabbit oxidase will be applied to the studies proposed with the different forms of the human enzymes. Preliminary experiments with crude mitochondrial preparations of human brain MAO have already revealed that the human oxidase is sensitive to a variety of tricyclic drugs. It is hoped the present studies will help establish whether tricyclic antidepressant drugs at concentrations which are likely to occur in patients receiving these drugs can inhibit either or both forms of the human brain oxidase.